Deciphering how naturally occurring sequence features impact the phase behaviors of disordered prion-like domains

Prion-like low complexity domains (PLCDs) have distinctive sequence grammars that determine their driving forces for phase separation. Here, we uncover the physicochemical underpinnings of how evolutionarily conserved compositional biases influence the phase behavior of PLCDs. We interpret our results in the context of the stickers-and-spacers model for phase separation of associative polymers. We find that tyrosine is a stronger sticker than phenylalanine whereas arginine is a context dependent auxiliary sticker. In contrast, lysine weakens sticker-sticker interactions. Increasing the net charge per residue destabilizes phase separation while also weakening the strong coupling between single-chain contraction in dilute phases and multi-chain interactions that give rise to phase separation. Finally, glycine and serine residues act as non-equivalent spacers, thus making glycine vs. serine contents an important determinant of the driving forces for phase separation. The totality of our results leads to a set of rules that enable comparative estimates of composition-specific driving forces for PLCD phase separation.